Access to P-chiral phosphine oxides by enantioselective allylic alkylation of bisphenols

Article abstract of DOI:10.1039/C8SC05439H

A novel biscinchona alkaloid-catalyzed highly enantioselective desymmetrization reaction of bisphenol compounds with achiral Morita-Baylis-Hillman carbonate agents was developed. Through the asymmetric allylic alkylation strategy, a broad range of optical

Full text of DOI:10.1039/C8SC05439H

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DOI: 10.1039/C8SC05439H
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Access to P-Chiral Phosphine Oxides by Enantioselective Allylic
Alkylation of Bisphenols
Guo Hui Yang, Yao Li, Xin Li* and Jin-Pei Cheng
Received 00th January 20xx,
Accepted 00th January 20xx
A novel biscinchona alkaloid-catalyzed highly enantioselective desymmetrization reaction of bisphenol compounds with
achiral Morita–Baylis–Hillman carbonate agents was developed. Through the asymmetric allylic alkylation strategy, a broad
range of optically active P-stereogenic phosphine oxides were generated with excellent to good yields (up to 99%) and high
enantioselectivities (up to 98.5:1.5 e.r.). The reaction was further investigated by the linear free energy relationship (LFER)
analysis. A possible transition state was proposed and furthered verified by theoretical calculations.
DOI: 10.1039/x0xx00000x
www.rsc.org/
atroposelective
construction
of
axially
chiral
anilides (Scheme 1b).12
Introduction
In continuation of our ongoing interest in AAA strategy,
we speculated that the privilegedphosphorus compounds
with P-stereogenic centers could be generated via AAA reaction
between bis(2-hydroxyphenyl) phosphinates and achiral MBH
carbonates (Scheme 1b). Thus, two challenges need to be
solved in this scenario: i) the difficulty in controlling
stereoselectivities due to the lack of chirality at the bonding
site; ii) the difficulty in designing a proper chiral catalyst to
induce enantiocontrol during the course of desymmetrization,
because the targeted phosphorus center is remote from the
enantiotopic site. Herein, we reported a biscinchona alkaloid-
catalyzed enantioselective desymmetrization of bis(2-
hydroxyphenyl) phosphine oxides. Utilizing the AAA strategy
based method, a number of phosphine oxides processing chiral
phosphorus (V) atoms were synthesized with good
enantioselectivities.
P-stereogenic compounds, in which the chirality is on the
phosphorus atom, have been widely used as biologically active
compounds,1 chiral ligands2 and useful building blocks3. The
significance of this privileged structural motif with P-
stereogenic center has led to a great demand for efficient
synthetic methods. However, the methodologies used to
synthesize such chiral structures were largely limited.4 Early
reports on P-stereogenic center synthesis comprise the
resolution of diastereoisomers,5 chiral auxiliary controlled
asymmetric
reactions,6
transition-metal-catalyzed
enantioselective cross-couplings,7 asymmetric addition
reactions of phosphorus nucleophiles,8 and desymmetrization
of prochiral phosphorus derivatives (Scheme 1a).9 Among these
above mentioned synthetic strategies of P-stereogenic centers,
only two cases were achieved through organocatalysis.10
Therefore, it is currently desirable and challenging to develop
an organocatalysis-based synthetic methodology for P-
stereogenic centers, and to expand the facile and extensive
substrate adaptability.
(a) General strategy for the synthesis of P-stereogenic compounds
Resolution
Limitations:
O
P 
R2
Chiral auxiliary
Harsh reaction conditions
Lewis base catalyzed asymmetric allylic alkylation (AAA)
reaction with Morita–Baylis–Hillman (MBH) carbonates as
electrophile precursors has been considered as one of the most
attractive approach to build stereogenic centers. However, the
AAA strategy currently was restricted to the build of chiral
carbon centers because most frequently used allylation
reagents are racemic MBH adducts. In fact, it is possible to
expand the usage of AAA strategy to building other non-carbon
center chirality when the reactions proceed between achiral
MBH adducts and N (O or S) type nucleophiles. Our group
recently developed a general and efficient method for
R1
R3
Enantioselective cross-couplings
High cost of catalysts
Requiring additive agents
Asymmetric addition
Desymmetrization
(b) "AAA" strategy for the construction of P-stereogenic centers
O
R4O2
C
N
R
Our previous work
:
"N" nucleophile
R5
OBoc
N (O or S) type
nucleophiles
CO2R4
CO2R4
Axially chiral anilides
Lewis Base
-CO2
+
OtBu
N
CO2R4
This work
:
OH
O
P
O
"O" nucleophiles

R6
R7
R7
Challenges:
no chirality at bonding site
potential phosphorus chiral center remote from the bonding site
P-chiral phosphine oxides
Scheme 1 Methods for the synthesis of P-stereogenic compounds.
a. State key Laboratory of Elemento-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071 (China). E-mail: xin_li@nankai.edu.cn
† Electronic Supplementary Information (ESI) available: experimental procedures,
characterization data and computational details. See DOI: 10.1039/x0xx00000x
Results and discussion
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Reaction optimization
1, entry 6). To further improve the enantioselectiVviietwy,Arwticele Othnleinne
screened different bisphenol substrates. To our delight,
DOI: 10.1039/C8SC05439H
Table 1 Reaction optimization.a
substrates 1b-1d, which had large size of the ester groups,
showed improved enantioselectivities (Table 1, entries 9-11).
This result indicated that the enantioselectivity of the studied
desymmetrization reaction may be closely related to the steric
hindrance of substituent linked to pre-stereogenic P-center.
This hypothesis was furthermore supported by reaction with
substrate phosphine oxide 1e, in which the enantioselectivity
was obtained as 84:16 e.r. (Table 1, entry 12). A series of
subsequent screenings (for example, temperature, solvent, and
substrate ratio) kept enhancing the enantioselectivity. Lowering
CO2Bn
OH HO
O
HO
O
O
OBoc
10 mol% cat.
P
+
CO2Bn
P
CH2Cl2, RT, 24 h
R1
R1
1
2a
3
4c:
(DHQD)2PHAL
(DHQD)2AQN
(DHQD)2PYR
(DHQ)2PHAL
(DHQ)2AQN
(DHQ)2PYR
N
OH
N
OH
4d:
4e:
4f:
O
o
H
the reaction temperature to -40 C can further increase e.r.
O
N
value to 94:6, while increasing catalyst loading and prolonging
the reaction time were necessary to ensure the conversion of
reaction (Table 1, entry 13). The evaluation of the solvents
showed that CHCl3 was the best reaction medium in terms of
reactivity and enantioselectivity (Table 1, entries 13-17). The
reaction also favoured the increased amount of substrate of 2a
with an improved yield to 84% with the retaining 94.5:5.5 e.r.
(Table 1, entry 18).
N
4g:
4h:
4a
4b
entry
R1
Cat.
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Yield (%)b
3a: 96
3a: 99
3a: 60
3a: 60
3a: 73
3a: 73
3a: 68
3a: 68
3b: 65
3c: 64
3d: 90
3e: 90
3e: 46
3e: 60
3e: 36
trace
e.r.c
50:50
1
2
1a: OMe
1a: OMe
1a: OMe
1a: OMe
1a: OMe
1a: OMe
1a: OMe
1a: OMe
1b: OEt
1c: OiPr
1d: OAd
1e: Ad
4a
4b
4c
4d
4e
4f
4g
4h
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
54.5:45.5
51.5:48.5
52:48
3
4
Substrate evaluation
5
53.5:46.5
66:34
Table 2 Substrate scope of phosphine oxide substrates.a
6
7
53:47
CO2Bn
8
53.5:46.5
68.5:31.5
70.5:31.5
71.5:28.5
84:16
OH HO
O
OBoc
O
HO
O
9
(DHQ)2PHAL (20 mol%)
CHCl3, -40°C, 6 days
P
+
CO2Bn
P
R1
10
11
12
13d
14d
15d
16d
17d
18d, e
R2
R2
R1
3
R2
R2
1
2a
3e
R1 = Ad R2 = H
R1 = Ad R2 = Me
R1 = Ad R2 = Et
84% yield, 94.5:5.5 e.r.
91% yield, 96:4 e.r.
3f
3g
1e: Ad
94:6
75% yield, 96.5:3.5 e.r.
71% yield, 97:3 e.r.
CO2Bn
HO
3h
R1 = Ad
R2 = iPr
1e: Ad
94.5:5.5
94:6
3i R1 = Ad R2 = cHex
64% yield, 95.5:4.5 e.r.
O
1e: Ad
THF
3j
3k R1 = Ad R2 = OMe
O
R1 = Ad R2 = tBu
34% yield, 92.5:7.5 e.r.
58% yield, 91.0:9.0 e.r.
65% yield, 88.5:11.5 e.r.
73% yield, 96:4 e.r.
P
1e: Ad
toluene
ether
Ndf
Ad
3l R1 = Ad
R2 = F
R2
R2
1e: Ad
trace
Ndf
3m
3n
3o
R1 = Ad R2 = Cl
3
R2 = Br
R1 = Ad
71% yield, 97.5:2.5 e.r.
66% yield, 98.5:1.5 e.r.
1e: Ad
CHCl3
3e: 84
94.5:5.5
R1 = Ad R2= I
a Reaction conditions: phosphinate 1 (0.1 mmol), MBH carbonates 2a (0.12
mmol), catalyst (10 mol %), in 1 mL of solvent. b Isolated yields. c Determined
by chiral HPLC analysis. d The reaction was conducted at -40 oC with 20 mol%
(DHQ)2PHAL and reaction time was 6 days. With 0.2 mmol 2a. Not
determined.
CO2Bn
CO2Bn
HO
O
HO
O
O
e
f
O
P
P
Ph Ph
Ph
R1 = Ph3C, R2 = H
R1 = t-Bu, R2 = H
3p
, 81% yield, 93:7 e.r.
3q
, 81% yield, 88.5:11.5 e.r.
Our initial investigation was carried out with bis(2-
hydroxyphenyl) phosphinates 1a and Boc protected MBH
product 2a as the model substrates, 10 mol% of cinchona
alkaloid 4a as catalyst in CH2Cl2 at room temperature. The
reaction gave the desymmetrization product 3a in 96% yield,
albeit with racemic result (Table 1, entry 1). To improve the
enantioselectivity, we next evaluated the different types of
cinchona alkaloid catalysts. As shown in Table 1, the catalysts’
backbone demonstrated remarkable impacts towards the
outcome of the reaction (Table 1, entries 2-8), in which
biscinchona alkaloid catalyst 4f gave the best 66:34 e.r. (Table
a Reaction conditions: phosphine oxides 1 (0.1 mmol), MBH carbonates 2a
(0.2 mmol), catalyst (20 mol%), 1 mL CHCl3. Isolated yields. e.r. values
were determined by chiral HPLC analysis.
With the optimal reaction conditions in hand, we set out to
explore the substrate generality of this desymmetrization
strategy. Firstly, different substituted phosphine oxides were
investigated. As shown in Table 2, substrates with electron-
donating groups and electron-withdrawing groups on the
phenyl ring were well tolerated in this reaction. The
corresponding products 3e-3k and 3l-3o were afforded in 34-
2 | J. Name., 2012, 00, 1-3
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91% yields and 91.0:9.0-98.5:1.5 e.r. values. When the
substituted atom was F, the enantioselectivity decreased to
moderate level (3l, 65% yield and 88.5:11.5 e.r.). It is valuable
to note that the steric hindrance of the substituent seems to
also influence on the reactivity. For example, the substrate with
R2 as tert-butyl group only provided corresponding product 3j
with 34% yield under the optimized reaction conditions. Other
two substrates with large steric hindrance phosphine oxides, in
which the groups linked to P-center were tert-butyl and
triphenyl methyl, were also examined. As a result, 3p was
obtained in 81% yield with 93:7 e.r. and 3q was obtained in 81%
yield with 88.5:11.5 e.r..
View Article Online
DOI: 10.1039/C8SC05439H
2.0
1.8
1.6
1.4
1.2
1.0
0.8
y = 0.96x - 0.01
R2 = 0.96
I
iPr
Me
NPA (O-)
Br
Cl
(C-O-)

H
Et
OH
O
O
cHex
P
tBu
Ad
R2
R2
OMe
Hammett constant

F
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Experimental ΔΔG‡(e.r.) Kcal/mol
Table 3 Substrate scope of MBH carbonate substrates. a
CO2R3
OH HO
O
OBoc
O
HO
y = 0.83x + 0.10
trityl
O
(DHQ)2PHAL (20 mol%)
CHCl3, -40°C, 6 days
P
+
CO2R3
1.0
0.9
0.8
0.7
0.6
0.5
0.4
R2 = 0.83
P
Ad
R2
R2
Ad
3
R2
R2
1
2
Ad
tBu
CO2-tBu
HO
OH
O
O
O
P
O
HO
O
O
P
R1
Ad
O
P
O
Ad
OEt
OMe
Sterimol parameter B1
OAd
R2 = H, R3 = t-Bu
R2 = Me, R3 =1-methylnaphthyl
3s
OiPr
3rb
, 61% yield, 92:8 e.r.
, 93% yield, 95.5:4.5 e.r.
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
R2 = Me, G = 2-CF3, 99% yield, 96:4 e.r.
, R2 = Me, G = 2-Me, 77% yield, 95.5:4.5 e.r.
, R2 = Me, G = 2-MeO, 46% yield, 96.5:3.5 e.r.
Experimental ΔΔG‡(e.r.) Kcal/mol
3t
,
3u
3v
HO
O
P
, R2 = Me, G = 2-Cl, 99% yield, 95.5:4.5 e.r.
R2 = Me, G =3-Me, 75% yield, 95:5 e.r.
R2 = Me, G = 3-MeO, 78% yield, 95:5 e.r.
R2 = Me, G =3-Cl, 88% yield, 96:4 e.r.
, R2 = Me, G =4-F,85% yield, 96:4 e.r.
, R2 = Me, G = 4-Cl, 99% yield, 96:4 e.r.
, R2 = Br, G = 2-Me, 52% yield, 96.5:3.5 e.r.
, R2 = Br, G =3MeO, 41%yield, 97.5:2.5 e.r.
, R2 = Br, G =4-F, 70% yield, 97:3 e.r.
3w
3x
,
R2
O
R2
O
2.0
3y
,
Ad
y = 0.96x - 0.01
R2 = 0.96
3z
,
O
I
3a'
3b'
3c'
3d'
3e'
1.8
1.6
1.4
1.2
1.0
0.8
G
3t-3e'
iPr
NPA (O-)

Me
Br
(C-O-)
Cl
a Reaction conditions: phosphine oxides 1 (0.1 mmol), MBH carbonates 2 (0.2
mmol), catalyst (20 mol%), 1 mL CHCl3. Isolated yields. e.r. values were
determined by chiral HPLC analysis. b The reaction was conducted at 0 oC
H
OH
O
Et
O
cHex
P
R1
PtBu
R2
R2
OMe
tBu
Sterimol parameter B1
Hammett constant
Further investigation of the substrate scope was focused on
the Boc protected MBH carbonate substrates 2 (Table 3). The
electronic nature or position of the substituent on the benzyl
ring do not appeare to affect the results, all the benzyl-
substituted MBH carbonates afforded the target products 3t-3e’
in moderate to excellent yields (41-99%) with excellent
enantioselectivities (95.5:4.5 to 97.5:2.5 e.r.). The 1-
methylnaphthyl type MBH carbonate tolerated well under the
optimal condition, gave 3s in 93% yield with 95.5:4.5 e.r.. The
tert-butyl substituted MBH carbonate is also transformed to the
desired product 3r in 61% yield and 92:8 e.r. by running the

F
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Experimental ΔΔG‡(e.r.) Kcal/mol
Fig. 1 Correlation of enantioselectivity with substrate parameters.
LFER researches
The substrate scope study reveals that, in general, product
with large size of the substituent on the aromatic ring of
phosphine has better enantioselectivity. To investigate the
effect of steric factor on the enantioselectivity, we plotted the
enantioselectivities towards Charton values.14 Preliminary
analysis revealed that substrates having large steric
substituents R2 gave better enantioselectivities (For R2 = H, Me,
Et, iPr, see Fig. S1 in SI). This rule could be also expanded to
o
reaction at 0 C albeit with the large steric hinderance. The
absolute configuration of 3r was determined by X-ray
diffraction analysis and those of other products were assigned
by analogy.13
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-
-
substrates containing halogen substituent (R2 = F, Cl, Br, I, see ΔΔG‡(e.r.) = -3.04σ + 78.6NPA(O ) - 0.014ν(C-O ) + 88V.i2ew Article O(n1lin)e
DOI: 10.1039/C8SC05439H
Fig. S2 in SI). It seemed that steric factor may play a role in
enantioselectivity control. However, the steric correlation could ΔΔG‡(e.r.) = 0.16B1 + 0.24
(2)
not explain the stereoselectivity for the substrates containing
-
-
other large hindrance substituents, such as R2 = tBu or cHex. ΔΔG‡(e.r.) = -3.03σ + 78.1NPA(O ) - 0.0144ν(C-O ) + 0.828B1 +
Thus, other factors, such as electronic effect, should also be 85.7
(3)
considered.
Theoretical calculations
Recently, Sigman and coworkers utilize multivariate linear
regression (MLR) models to effectively predict the experimental
Theoretical calculations were conducted to support the
reaction outcome based on both experimentally-derived and above analysis.17,18 Extensive explorations of a variety of
calculated physical organic molecular descriptors.15 Inspired by catalytic arrangements show that the most two stable transition
their work and our previous related study,12 we explored the state structures are TS1 and TS2 (Fig. 2). The free energy
factors that governing the stereoselectivity. The regression difference between TS1 and TS2 is 2.2 kcal/mol, which agrees
analysis was made with ten data and tested with one data. After with experiment data 85:15 e.r.. As shown in Figure 2, TS1 is
evaluating various parameters, Hammett constant (σ), NPA stabilized by a C−H···π interaction between the methylene of
charge (O-) and ν (C-O-),15b and 15c which can be used to embody quinuclidine ring and the aromatic ring of phenol. However, this
the steric and electronic effect, were found to accurately interaction is missing in TS2, which would be a key factor that
predict the stereoselectivity (eq 1, Figure 1, slope = 0.96, contributes to the energy difference between TS1 and TS2.
intercept = -0.01, R2 = 0.96). Besides, the effects of substituents Previous studies of C−H···π interactions showed that the
linked to pre-stereogenic P-center were evaluated. The interaction energies are correlated with Hammett constant
stereoselectivity is in good correlation with Sterimol parameter (σm),19 which supported our LFER analysis. The steric factor of
B1 (eq 2).16 The steric factor of substituents linked to substituents linked to pre-stereogenic P-center could be also
phosphorous atom significantly affected the enantioselectivity. explained by transition states. If the tert-butyl group linked to
Finally, based on eq 2, the eq 1 could be expanded to substrates phosphorous atom is replaced by adamantyl group, the steric
that have different substituents linked to pre-stereogenic P- effect between catalyst and substrate will destabilize TS2, which
center (eq 3, slope = 0.96, intercept = -0.01, R2 = 0.96).
is crucial for excellent enantioselectivity control.
2.14
2.00
2.47
TS1
G‡ = 0.0
TS2
G‡ = 2.2



O
O
O
O
O
O
O
H
P
N
P
O
N
N
O
O
O
O
O
N
N
O
H
H
N
N
N
N
O
O
O
O
N
N
N
Fig. 2. Transition state structures and relative free energies (in Kcal/mol) for desymmetrization catalyzed by 4f. Noncritical hydrogen atoms have been omitted for clarity.
The C-H···π interaction in TS1 is highlighted.
Large scale reaction and product transformation
4 | J. Name., 2012, 00, 1-3
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Ph
Ph
P
Ph
To probe the efficiency of current studied desymmetrization
strategy in preparative synthesis, large scale reactions were
investigated under the optimal conditions. To our delight, the
desired products 3e and 3f were obtained without any loss of
enantioselectivities (Scheme 2). Further bromation of 3f by 1.5
equiv NBS afforded 4b. Treated 4b with 5 equivalent DMAP
acquired 5b in moderate yield with retentive enantioselectivity.
Finally, product 7b can be obtained in 90% yield with 96.5:3.5
e.r. under the conditions shown in Scheme 2. The preliminary
application of the synthesized bidentate chiral phosphine oxide
indicated that 7b could be used as a catalyst in asymmetric
reactions between enone and aldehydes (Scheme 2).20
Ad
Ad
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P
P
OBoc
O
ODOI: 10+.1039/C8SC0O5439H
Hydroquinine (10 mol%)
CH2Cl2, RT, 12 h
+
CO2Bn
OH
O
OH
CO2Bn
_
+
11
2a
12,
11',
(
)
40% yield,
>19:1 dr, 64.5:35.5 e.r.
55% yield,
>19:1 dr, 68.5:31.5 e.r.
Scheme 3 Kinetic resolution experiment using AAA strategy..
Conclusions
In summary, we have developed a catalytic enantioselective
desymmetrization of bisphenols that hold pre-stereogenic P-centers,
using a biscinchona alkaloid catalyst. This AAA strategy based
method provides a novel and highly efficient way to the synthesis of
P-stereogenic compounds, affording the desired functionalized
phosphine oxides in good yields (up to 99%) and high
enantioselectivities (up to 98.5:1.5 e.r.). A range of functional groups
were tolerated under the mild reaction conditions. A possible
transition state was proposed based on the linear free energy
relationship analysis, which was further verified by theoretical
calculations.
CO2Bn
OH HO
O
OBoc
O
HO
O
standard conditions
P
+
CO2Bn
P
Ad
R
R
Ad
R
R
1e
2a
3e or 3f
0.5 mmol
1.0 mmol
3e R = H,
3f R = Me,
:
:
71% yield, 94.5:5.5 e.r.
89% yield, 96.0:4.0 e.r.
Conflicts of interest
CO2Bn
CO2Bn
HO
There are no conficts to declare.
O
HO
O
O
Br
NBS (1.5 equiv)
O
P
P
CH2Cl2, RT, 3 h
87% yield
Ad
Ad
4b
Acknowledgements
3f
3f
: 89% yield, 96.0:4.0 e.r.
84% yield, 96.0:4.0 e.r.
We are grateful to the NNSFC (Grant No. 21390400) for financial
support.
5.0 equiv DMAP
CH2Cl2, RT, 2 h
Ph
O
P
Ph
O
DCC (1.2 equiv)
DMAP (0.1 equiv)
CH2Cl2, RT, 8 h
OH HO
O
Br
O
HO
Br
O
Notes and references
P
O
P
P
Ad
Ph
CO2H
Ph
Ad
7b
1
2
3
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5b
67% yield
90% yield, 96.5:3.5 e.r.
6b
O
O
O
OH
7b
15 mol%
4 equiv HSiCl3


+
Ar
H
Ar
CH2Cl2:CH3CN = 1:1, RT, 12h
Ph
0.24 mmol
8
, 0.2 mmol
O
OH
O
OH
*
*
*
*
O
Ph
Ph
9
10
, 63% yield, 75:25 dr,
51.0:49.0 e.r./62.5:37.5 e.r.
, 59% yield, 53:47 dr,
53.0:47.0 e.r./55.5:45.5 e.r.
Scheme 2 Large scale reaction and synthetic transformations of the product.21
Moreover, we also made another kinetic resolution
experiment with substrate (±)-11, which cotains both axial and
phosphorous pre-chirality (Scheme 3). The reaction of (±)-11
with 2a proceed smoothly in the presence of 10 mol%
hydroquinine under the standard conditions, resulting in 12 in
40% yield with 64.5:35.5 e.r. and 11’ in 55% yield with 68.5:31.5
e.r.. Further optimization of reaction conditions may lead to
better enantioselectivities. This result again proves the
universality of the strategy for the synthesis of P-stereogenic
compounds.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Chemical Science
Page 6 of 7
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21 For details of derivatization, see ESI.
6 | J. Name., 2012, 00, 1-3
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Chemical Science
View Article Online
DOI: 10.1039/C8SC05439H
AAA Strategy for the Construction of P-Stereogenic Centers
OH HO
CO2R3
HO
O
OBoc
CO2R3
O
(DHQ)2PHAL
CHCl3, -40°C
P
R1
O
+
P
R2
R2
R1
R2
R2
up to 99% yield
up to 98.5:1.5
e.r.
Challenges:
no chirality at bonding site
potential phosphorus chiral center remote from the bonding site
A biscinchona alkaloid-catalyzed AAA reaction for the construction of P-stereogenic center
compounds was developed.